16-methyl-17alpha-hydroxy-3, 20-diketopregnanes



United States Patent Q 3,055,922 16-NlETHYL-17oc-HYDROXY-3,20- DH ETOPREGNANES Lawrence S. Levinson, Scotch Plains, N.J., assignor to Olin Mathieson Chemical Corporation, New York,

N.Y., a corporation of Virginia No Drawing. Filed Aug. 28, 1961, Ser. No. 134,083 2 Claims. (Cl. 260-39745) This invention relates to, and has for its objects the provisions of a method of preparing physiologically active steroids, and to the physiologically active steriods produced thereby.

It is known that various 16-methylated steroids of the 17u-hydroxy3,20-diketo-A -pregnene series are physiologically active substances which possess glucocorticoid and anti-inflammatory activities. It has now been found that if the A-ring of such steroids is saturated, thereby yielding corresponding i16-methylated steroids of the 17a-hydroxy- 3,20-diketopregnane series, the topical anti-inflammatory activity of the starting A -pregnene derivatives is surprisingly retained, although the systemic activity of these compounds is for all practical purposes eliminated. This discovery is unexpected, since a priori it would have been assumed that'all anti-inflammatory activity, both systemic and topical, would be lost when the A-ring was saturated. Moreover, since the saturated pregnane steroids of this invention lack any significant systemic activity, they are compounds of choice for the topical treatment of such skin conditions as dermatitis, sunburn, neurodermatitis, eczema and anagenital pruritus. For these purposes they may be administered topically in the usually topically acceptable formulations, the dosage being adjusted for the relative activity of the particular steroid and the condition being treated.

Although the compounds of this invention include any 16-methyl-17a-hydroxy-3,ZO-diketopregnane steroid, the preferred compounds are those of the general formula wherein R is hydrogen, R is fi-hydroxy, or together R and R is keto; X is hydrogen, chloro, of fluoro; Y is hydrogen or methyl; Y is in either the alpha or beta position and represents hydrogen, halogen (preferably chloro or fluoro) or lower alkyl (preferably methyl); and Z is hydrogen, chloro, fiuoro, hydroxy or acyloXy. Particularly preferred are compounds wherein R is hydrogen, R is B-hydroxy or together R and R is keto; X is fluoro; Y is hydrogen; Y is hydrogen or fluoro; and Z is hydroxy or acyloxy.

The compounds of this invention can be prepared in accordance with the method of this invention by hydro genating the corresponding 16-methyl-17ot-hydroXy-3,20- diketo steroids of the M-pregnene (including the A -pregnadiene and A -pregnatriene) series. The reduction is accomplished by treatment with hydrogen in the presence of a hydrogenation catalyst such as a noble metal catalyst (e.g. palladium on a carrier or ruthenium on a carrier). The amount of hydrogen which will be absorbed depends of course on whether a pregnene, pregnadiene or pregnatriene is employed as the starting steroid. Thus, theoretically if a pregnene is used, one mole of hydrogen is absorbed per mole of steroid; a pregnadiene uses two moles of hydrogen per mole of steroid; and a pregnatriene, three moles of hydrogen per mole of steroid. Particularly preferred as starting steroidal materials for the process of this invention are steroids of the general formula wherein the 1,2 and 6,7 positions are saturated or doublebonded and R, R, X, Y, Y and Z are as hereinbefore defined.

Among the suitable starting steroids utilizable in the first process of this invention may be mentioned:

16a-methylhydrocortisone, 16,8-methylhydrocortisone, 16a-methylcortisone,

IGB-methylcortisone,

16a-methylprednisolone,

l6fi-methylprednisoline,

l6a-methylprednisone,

9tx-halo-1u-methylhydrocortisones (i.e. 9a-fluoro-l6amethylhydrocortisone, 9a-chloro-16amethylhydrocortisone, 9a-bromo,16a-methylhydrocortisone and 9oc-i0d0- 16u-methylhydrocortisone) 9a-halo-l6a-methylcortisones,

9a-halo-16u-methylprednisolone (e.g. dexamethasone),

9u-halo-16ot-methylprednisones,

9-a-halo-16fl-methylhydrocortisones (e.g. 9oc-fll1OI'O-16 3- methylhydrocortisone),

9a-halo-16fi-methylcortisones (e.g. 9a-chloro-16fi-methylcortisone), Y

9u-halo-16(3-methylprednisolones (e.g. 9a-fluoro-16,8-

methylprednisolone) 9u-halo-16fi-methylprednisones,

Got-16oc-dimethylhydrocortisone,

6a-16u-dimethylcortisone,

6,8,16fi-dimethylprednisolone,

6a-l6a-dimethylprednisone,

2a,16ot-dimethylhydrocortisone,

2w]6 3-dimethylcortisone,

2,16a-dimethylprednisolone,

2,16a-dimethylprednisone,

2a,6u,16a-trimethylhydrocortisone,

2a,6tx,16u-trimethylcortisone,

9ot-halo-2,16a-dimethylprednisolones (e.g. 2-methyldexamethasone),

9ot-halo-6a,16ot-dimethylhydrocortisones (e.g. 9a-fluoro- 6a,16wdimethylhydrocortisone) 9a-halo-6u,16a-dimethylprednisolones (e.g. 6a,16-methyldexamethasone),

16a-methyl-6-dehydrocortisone,

16ot-methyl-G-dehydrohydrocortisone,

16u-methyl-6-dehydroprednisolone,

9a-halm16a-methyl-G-dehydroprednisolones,

-which are formed with l6a-methyl-9u-halo-1 1p,17a-dihydroxyprogesterones (e.g. 16a-methyl-9a-chloro-1 113,l7u-dihydroxyprogesterone and 16a-methyl 9oz-fluOIO-l1}3,17oz-di l1ydlOXyprogesterone),

16a-methyl 9a-halo-17a-hydroxy-1 l-keto-progesterones (e. g. 16oc-II16thYl-9oc-fll1010-17oc-hyd1OXy-1 l-ketoprogesterone) 16a-methyl-9oc-halo-1 1 B-17a-dihydroxy-l-dehydroprogesterones (e. g. 16a-methyl-9a-fluoro-l15,17a-dihydroXyl-dehydroprogesterone) 16[3-methyl-9a-halo-11p,17a-dihydroxyprogesterones (e. g. 165-methyl-9a-fiuoro-11fl, 17a-dihydroxyprogesterone) 1613-methyl-9a-halo-1lfl,17a-dihydroxy-l-dehydroprogesterones (e. g. 165-methyl-9e-fluoro-l1B,17a-dihydroxyl-dehydroprogesterone) 16a-methyl-21-halo- 1 15,17a-dihydroxyprogesterones e. g.

l6a-methyl-21-fluoro-11B,17a-dihydroxyprogesterone) 16a-methyl-21-halo-11B,17a-dihydroxy-l-dehydroprogesterones,

l6a-methyl 9a,21-dihalo-1 1B,17a-dihydroxyprogesterones e.g. 16u-methyl-9a,2l-difluoro-l15,17a-dihydroxyprogesterone) 9a,2l-dihalo-6oc,16a-dimethyl-l1}S,17u-hydroxy-l-dehydroprogesterones,

16e-hydroxy-6e-halo-16a-methylhydrocortisones (e. g. 60;- fluoro-l 6a-methylhydrocortisone and 6a-chloro-16amethylhydrocortisone) 6a-halo-l 6a-methylcortisones,

6a-halo-16oc-methylprednisolone,

Goa-halo-l6a-methylprednisone,

6u,9a-dihalo-16a-methylhydrocortisone (e.g. 611,9 oc-diflL'lO- ro-16oc-methylhydrocortisone) 6a,9a-dihalo 16a-methylcortisone,

6oc,9oc-dlhalO-l 6u-methylprednisolone' (e. g. 6a,9a-difluoro- 16u-methylprednisolone) 6a,9 a-dihalo-l 6u-methylprednisone,

2a,16a-dimethyl-6u-fluoro-hydrocortisone,

2a,l 6a-dimethyl-6a-fluorocortisone,

16a-methyl-6a-fluoro-1 1B,17a-dihydroxyprogesterone,

l6a-1'I16thYl-6oc-flUOYO-l 1-keto-17a-hydroxyprogesterone, 16a-methyl-6a fluoro-11f3,17a-dihydroxy-l-dehydroprogesterone,

16a-methyl-6a-fluoro-1 1-keto-17 a-hydroxy-l-dehydroprogesterone,

' 16a-methyl 6a,9a-dihalo-11B,17a-dihyd1'oxyprogesterone (e.g. 16u-methyl-6e,9u-difluoro-115,17a-dihydroxyprogesterone),

16a-methyl-6a,9u-dihalo-1 15,17a-dihydroxy-l-dehydroprogesterone (e.g. l6u-methyl-6a-9a,difluoro-1113,170:- dihydroxyl-dehydroprogesterone) 16B-methy1-6a-halohydrocortisone (e.g. 16/3-methy16a-fluoro-hydrocortisone) 16B-methyl-6a-halo-cortisone,

16 3-methyl-6u-haloprednisolone,

16B-methyl 6a-halo-prednisone,

16B-methyl-6a,9a-dihalohydrocortisone (e.g. 16fi-methyl- 6a,9a-difluorohydro cortisone) 1613-methyl-6a,9a-dihalocortisone,

l6fl-methyl-6a,9u-dihaloprednisolone (e.g. 16fi-methyl-6achloro-9u-fiuoro-prednisolone) I l6;3-methyl-6a,9a-dihaloprednisone,

and 21-esters of those compounds containing a 21-hydroxy group.

Among the suitable 21-esters can be mentioned those the acyl radical of: (a) a hydrocarbon monocarboxylic acid of less than twelve carbon atoms, such as an alkanoic acid (e.g. acetic, propionic, tert.-pentanoic, enanthic, and undecanoic acid), a monocyclic aryl carboxylic acid (e.g. benzoic and toluic acid), a monocyclic aryl lower alkanoic acid (e.g., phenacetic and fl-phenylpropionic acid), a lower alkenoic acid (e.g., undecenoic acid), a cycloalkane carboxylic acid, or a cycloalkenecarboxylic acid; (b) a hydrocarbon dicarboxylic acid of less than twelve carbon atoms, such as a lower alkanedioic acid (e.g., oxalic, malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic and sebacic acid), a lower alkenedioic acid (e.g., maleic, fumaric and citraconic acid), a cycloalkanedioic acid, a cycloalkenedioic acid, and a monocyclic aromatic dicarboxylic acid (e.g., the phthalic acids), as well as salts thereof with suitable bases such as inorganic bases, such as ammonium hydroxide, the alkali metal hydroxides (e.g., potassium hydroxide and sodium hydroxide) and the alkaline earth metal hydroxides; and organic bases, such as di(lower alkyl)- amines and heterocyclic amines (e.g., pyridine); and (c) phosphoric acid.

The 21-esters can also be prepared from the corresponding 21-hydroxy-5a-pregnanes by treatment of the latter with an acyl halide (preferably acyl chloride) or acid anhydride of one of the hydrocarbon monocarboxylic acids of less than twelve carbon atoms mentioned hereinbefore, one of the hydrocarbon dicarboxylic acids of less than twelve carbon atoms mentioned hereinbefore, or phosphoric acid, the reaction being conducted under the usual acylating conditions.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 9u-Flu0ro-1 6a-Methyl-5a-Pregnane-1 113,1 7a,21-Triol- 3 ,2 O-Dione A suspension of 3 g. of 5% palladium on barium sulfate in ml. of ethyl acetate is agitated in an atmosphere of hydrogen until hydrogen is no longer absorbed m-l.). To this suspension is added a suspension of 10 g. of dexamethasone in 900 ml. of ethyl acetate and the mixture agitated until hydrogen is no longer absorbed (1200 ml.). The mixture is filtered, washed well with ethyl acetate and hydrogenated again for 24 hours with 3 g. of fresh palladium on barium sulfate catalyst. Eighty-seven milliliters of hydrogen are taken up. The mixture is filtered and the solvent removed, in vacuo. The crude residue on recrystallization from acetonehexane furnishes analytically pure material in almost quantitative yield.

EXAMPLE 2 Following the procedure of Example 1 but substituting 10 g. of 9a-fluoro-16u-methylhydrocortisone for the dexamethasone the same product is formed in quantitative yield.

EXAMPLE 3 Following the procedure of Example 1 but substituting 10 g. of 9a-fluoro-16a-methyl-A -pregnatriene-1113,17u, 21-triol-3,20-dione for the dexamethasone, the same product is formed.

EXAMPLE 4 9u-Flu0r0-1 6oc-Methyl-5oc-Pregnane-1 70:,21-di0l- 3,11,20-Tri0ne Following the procedure of Example 1 but substituting 10 g. of 9a-fluoro-l6a-methylcortisone for the dexamethasone, 9u-fiuoro-16u-methyI-Sa-pregnane-17a,21-diol- 3,11,20-trione is obtained.

EXAMPLE 5 16a-Methyl-5a-Pregnane-1 1,3,1 70;,21 -Tri0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 16a-methylprednisolone for the dexamethasone, 16a-methyl-5a-pregnane-11p,17a,21-triol-3,20-dione is obtained.

EXAMPLE 6 1 6a-Methyl-9oc-Chlor0-5oa-Pregnane-1 70:,21-Di0l- 3,11 ,ZO-Trione Following the procedure of Example 1 but substituting 10 g. of 16a-methyl-9a-chloro-16u-hydroxyc0rtisone for the dexamethasone, 16ot-methyl-9ot-chloro-5a-pregnane- 17a,2l-diol-3,l1,20-trione is obtained.

EXAMPLE 7 Following the procedure of Example 1 but substituting 10 g. of l6fi-methyl-9a-fluoro prednisolone for the dexamethasone, 16,8-methyl-9a-fluoro-Swpregnane-1 1/3, 17u,21- triol-3,20-dione is obtained.

EXAMPLE 8 Following the procedure of Example 1 but substituting 10 g. of 16ot-rnethyl-9a-fluoro-A -pregnene,11,8,17a-di01 3,2()-dione for the dexamethasone, 9a-fluoro-16fi-methylu-pregnane-11fl,17a-di0l-3,20-dione is obtained.

EXAMPLE 9 Following the procedure of Example 1 but substituting 10 g. of 16B-methyl-9a-fiuoro-M-pregnene-115,17oa-di0l- 3,20-dione for the dexamethasone, 9a-fluor0-16fl-methyl- Sa-pregnane-I1B,17oc-diol-3,20-dione is obtained.

EXAMPLE 10 6 11,1 6a-Dimethyl-5oc-Pregnane-11B,17a,21 -Tri0l- 3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 60z,16wdimelhyl-9owfluOrO-PlfidlllSOlOHG for the dexamethasone, 6a,16a-dimethyl-9a-fiuQro-Sa-pregnane- 1lfi,17a,2l-triol-3,20-dione is obtained.

EXAMPLE 12 16fi-Methyl-5a-Pregnane-1 1,8,1 711,21 -Tri0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 16,6-methylprednisolone for the dexamethasone, 16 3-methyl-5a-pregnane-11,6,17a,21-triol-3,20-dione is obtained.

EXAMPLE 13 Following the procedure of Example 1 but substituting 10 g. of 16B-methyl-9a-chlorocortisone for the dexamethasone, l6 8-methyl-9a-chloro-S'a-pregnane-17a,21-diol-3,11, 20-trione is obtained.

EXAMPLE 14 6fi,16fi-Dimethyl-Sa-Pregnane-I 1,8,1 7a,21-Tri0l-3, 20-Dione Following the procedure of Example 1 but substituting 10 g. of the acetophenone derivative of 6,8,l6 8-dimethylprednisolone for the dexamethasone, GBJGB-dimethyI-Sapregnane-l1/3,17u,21-trio1-3,20-dione is obtained.

EXAMPLE 15 Following the procedure of Example 1 but substituting 10 g. of 9oz-fluoro-6u,16 3-dimethyl-prednisolone for dexamethasone, 9a -fiuoro-6u-1 6fi-dimethyl-5a-pregnane-l 1 3, 17u,21-triol-3,20-dione is obtained.

EXAMPLE 16 16a-Methyl-9oc-Chl0r0-5rx-Pregnane-I1 6,1 7 Ot-DiOl-3, 20-Dione Following the procedure of Example 1 but substituting 10 g. of 16u-methyl-9u-chloro-11fi,17u-dihydroxyprogesterone for the dexamethasone, 16a-methyl-9a-chlor0-5apregnane-l1 8,17a-diol-3,20-dione is obtained.

EXAMPLE 17 16a-Methyl-9oc-Flu0r0-5a-Pregnane-J 7 a- Ol-3,1 1,20-Tri0ne Following the procedure of Example 1 but substituting 10 g. of 16u-methyl-9ot-fluoro-A -pregnene-17a-ol-3,11,20- trione for the dexamethasone, l6a-methyl-9a-fluoro-5upregnane-17a-ol-3,11,20-trione is obtained.

EXAMPLE 18 9a-Fluoro-1 6 Oc-M ethy l-5 a-Pregnan 2-] 1,6,1 7 0:,21 -Tri0l- 3,20-Dione 21 -Acetate Following the procedure of Example 1 but substituting 10 g. of dexamethasone 2l-acetate for the dexamethasone, c fluoro-16a-methyl-5a-pregnane-11/3,17 x,21-triol-3,20- dione 21-acetate is obtained.

EXAMPLE 19 16a-Methyl-9a-Fluoro-5m-Pregnane-Z1,8,1 70:,2] -Triol-3,

20-Di0ne 21 -H emisuccinic Acid Following the procedure of Example 1 but substituting 10 g. of dexamethasone ZI-hemisuccinic acid for the dexamethasone, 16oc-methyl-9a-fiuoro-Sa-pregnane-l 1B,170c,21 triol-3,20-d.ione 21-hemisuccinic acid is obtained.

EXAMPLE 2O 16ot-Methyl-9a-Fluoro-Sa-PregnaneJ1fi,17a,21-Triol-3, 20-Dione 21 -Sodium H emisuccinate (a) Preparation of 16u-methyl-9a-flu0r0-5a-pregnane 115,17a,21-tri0l-3,20-di0ne 21 -hemisuccinic acid. -A solution of 4 g. of 16a-methyl-9'ot-fluoro-5a-pregnane 113,17, 2l-triol-3,20-dione and 8 g. of succinic anhydride in 40 ml. of anhydrous pyridine is heated at 60 for two hours. After cooling to 15, 20 g. of ice is added and the mixture poured slowly with stirring onto 150 ml. of crushed ice, containing 16 ml. of concentrated sulfuric acid. The resulting precipitate of the 21-hemisuccinic acid is filtered and washed well with water until free from sulfuric acid.

(b) Preparation of 16a-methyl-9u-flu0r0-5u-pregnane- ]1/8,]7u,21-tri0l-3,20-di0ne ZJ-sodium hemisuccinate.- 500 mg. of the 2l-hemisuccinic acid obtained in step a is dissolved in a minimum of alcohol and the resulting solution is neutralized with 0.1 N sodium hydroxide solution. The neutralized solution is freed from alcohol in vacuo, extracted with chloroform to remove residual unneutralized acid and the aqueous solution lyophilized in high vacuum. The residual material represents the pure sodium salt.

EXAMPLE 21 16ot-Methyl-9u-Flu0r0-5oc-Pregnane-IL8,17ot,2l-Triol-3, 20-Di0ne 21-S0dium o-Hemiphthalate Following the procedure of Example 20 but substituting 10 g. of phthalic anhydride for the succinic anhydride in step a, there is obtained l6a-methyl-9a-fluoro-5a-pregnane- 11B,l7oc,2l-triol-3,20-dione 2l-sodium-o-hemiphthalate.

7 EXAMPLE 22 1 6 oc-M ethyl 9u-Flu0r0-5oc-Pregnane-1 1[3,17a,21-Triol-3, 20-Dione 21 -Potassiumi H emigl utarate Following the procedure of Example 20 but substituting 10 g. of glutaric anhydride for the succinic anhydride in step a, and 0.1 N aqueous potassium hydroxide for the sodium hydroxide in step b, there is obtained 16 xmethyl 9a fluoro a pregnane-l15,l7a,21-triol-3,20-dione 21- potassium hemiglutarate.

EXAMPLE 23 Following the procedure of Example 1 but substituting g. of l6a-methyl-9a,21-difiuoro-A -pregnadiene-l1B, 17a-diOl-3,20-dl0ne for the dexamethasone, 16a-methyl- 901,2l-difluoro-Su-pregnane-l1B,l7a-diol-3,20-dione is obtained.

EXAMPLE 24 16a-Methyl-9a-Flu0r0-21-Chl0r0-5a-Pregnane-1 1,8,1 7a- Dial-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of l6u-methyl-9a-fluoro-2l-chloro-A -pregnadiene- 11fi,l7a-diol-3,20-dione for the dexamethasone, 160cmethyl 9'a-fluoro-2l-chloro-Sa-pregnane-l1,9,17a-diol-3, ZO-dione is obtained.

EXAMPLE 25 Bis-(1 6 oz-M ethyl 9a-Flu0ro-5a-Pregnane-1 16,1 70:,21-

Trial-3,20-Di0ne) 21 ,21 -Sulfite Following the procedure of Example 1 but substituting 10 g. of bis-dexamethasone 2l,2l-sulfite for the dexamethasone, bis-(16a-methyl 9a-fluoro-5a-pregnane-115, 17a,21-triol-3,20-dione) 2l,2l'-sulfite is obtained.

EXAMPLE 26 Bis*(1 6 a-M ethyl 9a-Flu0ro-5u-Pregnane-1 1 5,1 7a,21-

Trial-3,20-Di0ne) 21 ,21-Carbonate Following the procedure of Example 1 but substituting 10 g. of bis-dexamethasone 21,21-carbonate for the dexamethasone, bis-(16a-methyl 9-a-fluoro-5u-pregnane-1LB, 17a-21-triol-3,20dione) 21,21'-carbonate is obtained.

EXAMPLE 27 Bis- (1 6 u-M ethyl 9a-Flu0r0-5a-Pregnane-116,1 7 u,21 Trial-3,20-Dione) 21,21 -Sulfate Following the procedure of Example 1 but substituting 10 g. of bis-dexamethasone 2l,2l'-sulfate for the dexamethasone, bis-(16a-methyl 9a-fluoro-Su-pregnane-11/3, 17a,21-triol-3,20-dione) 2l,21-sulfate is obtained.

EXAMPLE 28 Bis- (16tx-Methyl-9a-Fluoro-5u-Pregnane-1 15,1 70:,21-

T rial-3,2 O-D ione) 21,21 -Phenylph0sphonate Following the procedure of Example 1 but substituting 10 g. of bis-dexamethasone 2l,21'-pheny1phosphonate for the dexamethasone, bis(16u,methyl-9a-fiuoro-5u-preg. nane-l 1B, l7a,21-trio1-3,20-dione) 21,21 '-phenylphosphonate is obtained.

EXAMPLE 29 16a-Methyl-9a-Fluoro-5u-Pregnane-I 1fl,1 711,2 1 -T riol- 3,20-Di0ne 21 -Potassium Phosphate To. a mixture of 3 ml. of anhydrous pyridine and 0.15 ml. of phosphorous oxychloride maintained at is added dropwise over a ten minute period a solution of 200 mg. of 16a-methyl-9a-fluoro-Set-pregnanc-l1 3,17a,2ltriol-3,20-dione in 3 ml. of pyridine. The resulting solution is allowed to remain at 15 for an additional minutes at which time 0.2 ml. of water is added and the mixture is allowed to warm up to room temperature.

One hour after the addition of water, the solution is concentrated in vacuo to about 2 ml., diluted with 10 ml. of water, extracted with chloroform and adjusted to a pH of 6.8 with potassium carbonate solution. The neutralized solution is lyophilized, triturated with alcohol and the alcoholic solution concentrated to small volume. The potassium salt of 16a-methyl 9a-fluoro-5a-pregnane-l1/3,- l7a,2l-triol-3,20-dione 2l-phosphate crystallizes under these conditions.

EXAMPLE 30 Following the procedure of Example 1 but substituting 10 g. of ou-fiuoro-dexamethasone for the dexamethasone, 16u-methyl 6a,9ocdifiuoro-5a-pregnane-11B,l7a,21-triol- 3,20-dione is obtained.

EXAMPLE 31 16 a-M ethyl-6 a,9a-D ifl [1070-5 a-Pregnane-I 1 5,1 711,21 Trial-3,20-Di0nc 21 Acetate Following the procedure of Example 1 but substituting 10 g. of 6a-fluorodexamethasone Zl-acetate for the dexamethasone, 16u-methyl 6a,9a-difluoro-5a-pregnane-l16,- l7a,2l-triol-3,20-dione 2l-acetate is obtained.

EXAMPLE 32 1 6 oc-M ethyl-6 13,9oc-D i flu0r0-5 a-Pregnane-l 1 [3,1 70:,21-

T rial-3 ,20-D ione Following the procedure of Example 1 but substituting 10 g. of 6(3-fluorodexamethasone for the dexamethasone, 16a-methyl-6B,9 x-difluoro-5a-pregnane- 115, 17a, 21-triol- 3,20-dione is obtained.

EXAMPLE 33 Following the procedure of Example 1 but substituting 10 g. of 16B-methyl-6a,9a-difluoro prednisolone for the dexamethasone, 16p-methyl-6a,9u-difiuoro prednisolone for the dexamethasone, 16/3-methyl-6u,9a-difluoro-5apregnane-l1p,17a,21-triol-3,20-dione is obtained.

EXAMPLE 34 1 6 a-M ethyl 6 u-Ch l0r0-9a-F luoro-S a-Pregnane-J 15,1 70:, 21-Tri0l-3,20-Dione wherein R is hydrogen, R is B-hydroxy and together R and R is keto; X is selected from the group consisting of chloro and fiuoro; Y is selected from the group consisting of hydrogen and methyl; Y is halogen; and Z is selected from the group consisting of hydrogen, chloro,

10 fiuoro, hydroxy and the acyloxy radicals of a hydro- 2,967,179 Arkley et a1 Jan. 3, 1961 carbon monoand dicarboxylic acids of less than twelve carbon atoms. FOREIGN PATENTS y -fi fl -p gn efi, 780,916 Great Britain Aug, 7, 1957 trio1-3,20-dione. 5

R f OTHER REFERENCES 6 ereuces cued m the file fth1s patent Chemerada et a1., J.A.C.S. 73, 4052-4053 1951 UNITED STATES PATENTS Loewenthal, Tetrahedron, vol. 6, N0. 4, June 1959, pp. 2,935,511 Taub et a1. May 3, 19 0 269403. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STERIODS OF THE GENERAL FORMULA 